This competitive renewal of our Program Project Grant, "Center of Excellence for Research on[unreadable] Complementary and Alternative Medicine (CAM) Antioxidant Therapies (CERCAT)," which was one of the[unreadable] first two CERCs funded by NCCAM in 2003, combines the scientific and research expertise of many faculty[unreadable] from the Linus Pauling Institute at Oregon State University and the clinical and medical expertise from faculty[unreadable] at Oregon Health & Science University. The Linus Pauling Institute has established itself as a national and[unreadable] international leader in research and education on micronutrients and antioxidants, and is one of a few[unreadable] research centers in the U.S. to focus entirely on increasing human "healthspan" - the period of a person's[unreadable] life during which they are generally healthy and free from serious or chronic illness - by dietary, lifestyle, and[unreadable] complementary medicine means. The results from the current funding period of the grant have lead to a[unreadable] paradigm shift in our understanding of how natural antioxidants function in the body, viz., not only by[unreadable] scavenging free radicals and preventing oxidative damage to biological macromolecules, but also through[unreadable] more subtle, yet profound changes in reduction-oxidation (redox)-sensitive processes inside cells. This new[unreadable] knowledge is fostering the development of new CAM modalities that reverse cell and tissue dysfunctions by[unreadable] "re-setting" intracellular signal transduction, transcription factor activation, and gene expression to normal,[unreadable] healthy levels. Hence, the goals of this competitive renewal of CERCAT are to better understand the[unreadable] molecular and cellular mechanisms of action and to test the in vivo efficacy - both in experimental animals[unreadable] and humans - of redox-active CAM modalities that have the potential to substantially improve the body's[unreadable] resistance to chronic disease and aging. These goals will be accomplished through three highly interactive[unreadable] projects: 1) "Lipoic acid supplementation to reduce risk factors for atherosclerosis in humans" (Dr. Balz Frei,[unreadable] Project Leader); 2) "Lower vulnerability to toxins in aging by treatment with lipoic acid" (Dr. Tory Hagen); and[unreadable] 3) "CAM antioxidants in amyotrophic lateral sclerosis" (Dr. Joseph Beckman). Center Investigators will be[unreadable] aided by an Administrative Core, which handles budgetary, reporting, and external advisory needs. In[unreadable] summary, CERCAT will provide an integrated set of mechanistic studies for the redox-active compound, (R)-[unreadable] a-lipoic acid, and other CAM antioxidants at the cellular and molecular level, and develop the proof of[unreadable] concept of their therapeutic value in suitable animal models and humans. We expect to make significant[unreadable] advances in the identification of the molecular and cellular mechanisms and relevant biological targets of[unreadable] these CAM antioxidants and - by discovering both beneficial and potentially harmful effects in vivo - to[unreadable] establish their safety and efficacy. This knowledge will help identify and develop new CAM modalities that[unreadable] enhance individual and public health and increase healthspan through affordable, safe, and effective means.